In a major operation (surgery), organs are temporarily put into an ischemic condition by ligating the blood vessel directly connected to organs and other method in order to control bleeding. The organs of such artificial ischemia suffer various injuries. Various injuries occur by a variety of causes after reperfusion of the blood in such organs.
Similar problems are encountered in organ transplantation. Extorpation of organs from an individual with cardiac standstill and application of the organs for transplantation (Non-heart Beating Donor Program: NHBD) have been noticed in recent years as a solution of lack of organs for transplantation. However, in the case of hepatic transplantation, for example, 30 minutes of warm ischemia and 12 hours of cold ischemia of the liver are the limit of NHBD for successful hepatic transplantation surgery even by using the latest surgical technology and preservation technology. The proportion of survival of the grafts one year after transplantation is less than 50%. Therefore, it is essential for realization of NHBD to alleviate warm ischemia injury occurred during the period from cardiac standstill to perfusion of the organ with a cold preservation solution, cold ischemia injury occurred thereafter in a cold preservation solution, and tissue injuries related to reperfusion of the blood after transplantation. Drugs having such actions known in the art include endotherin antagonist (J. Am. Coll. Surg., October 1997, Volume 185, 358–364), adenosine antagonist (Transplantation, Vol. 63, 217–223 No. 2, 1997), iron dependent lipid peroxidation inhibitor (Transplantation, Vol. 63, No. 2, p202–208, 1997) and the like.
While the compounds described in EP-620214 (Japanese Patent Laid-open No. 7-010838, U.S. Pat. No. 5,578,634), EP-620215 (Japanese Patent Laid-open No. 7-025850, U.S. Pat. No. 5,684,034), EP-675110 (Japanese Patent Laid-open No. 7-285933, U.S. Pat. No. 5,654,326), WO96/03120 (Japanese Patent Laid-open No. 10-505336), WO96/03376 (Japanese Patent Laid-open No. 10-503208, U.S. Pat. No. 5,641,800), WO96/03383 (Japanese Patent Laid-open No. 10-505584), WO97/21664 (EP-779271), WO97/21716 (EP-779273), WO98/18464 (EP-839806), WO98/24437 (EP-846687), WO98/24756, WO98/24794, WO98/25609, etc., parabromophenacyl bromide, mepaklin, manoaride, cherosin A1, etc. are known as sPLA2 inhibitors, these inhibitors have not been reported to have therapeutic or preventive actions for the ischemia reperfusion injury.
It is known that small intestine PLA2 activity increases by ischemia of the small intestines, and occurrence of lung injury accompanied by reperfusion of the small intestine can be prevented by administration of quinacrine, a PLA2 inhibitor (Am. J. Physiol., 268: G397, 1995). It is also reported that PLA2 which is increased by ischemia of the small intestine is mostly type-II (Journal of Japanese Surgery Association, Vol. 96, No. 12, p823, Dec. 1, 1995). However, these reports only describe prevention of injuries (indirect effects) of other organs such as lung caused by ischemia and reperfusion of local organs (the small intestines), and no descriptions are found about preventive effects (direct effects) of injuries at the local organs such as the small intestines suffering from ischemia. In other words, it is neither known that compounds having an sPLA2 inhibitory action, in particular compounds having type-II PLA2 inhibitory action, are useful as therapeutic or preventive drug for injuries caused in the organs suffering from ischemia, nor is suggested that such compounds are useful for the organs which are transplanted in the transplantation surgery or which may suffer from ischemia during the surgery.